1. Field of the Invention
The invention relates to a neuroprotective compound. The invention further relates to a morphinan compound used to treat a variety of neurological conditions, including Parkinson's disease or the symptoms of Parkinson's disease, learning and memory impairment in Alzheimer's disease, the symptoms of intoxication and or dependence on such narcotics as cocaine, morphine, and methamphetamine. The invention also relates to pharmaceutical formulations for such morphinan compounds.
2. General Background and State of the Art:
Dextromethorphan (DM; 3-methoxy-17-methylmorphinan) is a non-narcotic morphinan derivative widely used as an antitussive for almost 40 years. It has attracted attention due to its neuroprotective properties (5, 9, 17-20, 23, 24, 26, 27, 33, 34, 46, 50, 51). However, case reports of toxicity in children (43, 45); and phencyclidine (PCP)-like psychotomimetic reactions (8, 12, 44, 53) associated with high-dose DM ingestion are likely attributable to dextrorphan (DX; 3-hydroxy-17-methylmorphinan), which is a major metabolite of DM (50, 51). The DM dose for the neuroprotective effects (17-20, 50, 51) is much higher than the cough suppressant dosage. Clinically, high doses of DM can produce psychotropic effects (8, 12, 19, 43-45, 53). Furthermore, DM has been recognized as the object of drug-seeking behavior in several countries (19, 43, 45). Previously, it was suggested that DM potentiates the psychotropic effects induced by cocaine (13, 25), and that DM itself might produce psychotoxic effects in mice (12, 15, 20, 24, 27). Moreover, it was demonstrated that chronic DM administration perturbs the cellular immune response (16), and this is similar to the immunosuppressive effects caused by PCP (19). In the past decade, investigators have documented that DM has an N-methyl-D-aspartate (NMDA) receptor antagonistic effect with regard to neuroprotection (5, 9, 19, 20, 50). Therefore, a DM analogue that retains its neuroprotective activities without being converted into DX in vivo would be highly useful (7, 24, 27, 46, 50, 51).
Recently, a series of compounds that are modified in positions 3 and 17 of the morphinan ring system were synthesized, with the intention of developing compounds that retain anticonvulsant activity/neuroprotective property with negligible psychotropic effects (24). To reduce the PCP-like behavioral side effects (24, 39, 46), while retaining the anticonvulsant/neuroprotective effects, a series of 3- and 17-substituted morphinans were prepared that are structurally similar to DM, but are either not expected to be metabolized into DX or are expected to do so at a reduced rate compared to DM (24).
1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)(3, 40), lipopolysaccharide (LPS) (10, 28, 40) and methamphetamine (MA) (21, 22, 29) all cause degeneration of nigrostriatal dopaminergic neurons and loss of striatal dopamine in rodents, primates and other species (40). Accumulating evidence indicates that DM exerts antiparkinsonian effects in vivo (14, 47) and in vitro (33). In addition, DM improves levodopa associated motor fluctuations and dyskinesias in Parkinson's disease, although the narrow therapeutic index and psychotropic effects of DM limit its clinical usefulness (52).
Accordingly, there is a need in the neurobiology industry for a neuroprotective pharmaceutical compound that is substantially free of unacceptable side-effects, such as a compound that can treat the symptoms of Parkinson's disease without causing other negative psychological effects.